Early B-cell precursor leukemias revealed that the human immunoglobulin (Ig) genes rearrange in an ordered fashion such that heavy chain genes rearrange before light genes and kappa genes generally precede gamma. This ordered process includes an unanticipated deletion of the constant kappa (Ckappa) and kappa enhancer sequence prior to gamma rearrangement. We cloned three examples of the kappa-deleting element (Kde) which mediates this loss and found them to be identical. The Kde recombines site specifically with a conserved palindromic signal (CACAGTG) within the Jkappa-Ckappa intron and mediates all losses of kappa genes on nonexpressed alleles. This is an evolutionarily conserved element that helps ensure isotypic and allelic exclusion and may mediate the ordered use of light chain genes. We exploited Ig gene and T-cell receptor gene rearrangements to detect clonal evolution from diagnosis to relapse in acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, we exploited the sensitivity of this approach to identify large clonal populations in bone marrow during the presumed remission phase of ALL. We cloned the chromosomal breakpoint of the t(14;18)(q32;q21) translocation in human follicular lymphomas. The isolated 18q21 element mediates translocation in 60% of follicular lymphomas. The breakpoints cluster in a 4.0-kb region of chromosome 18 and within JH on chromosome 14 and suggest a site-specific recombination. Our 18q21 element contains a transcriptional unit and we have cloned cDNAs from this locus. As none of the known c-onc genes map to 18q21, this provides an opportunity to characterize a new transforming gene participating in the altered growth or differentiation of the t(14;18) lymphomas.